Pharmaceutical formulations intended to deliver drugs topically, either for local action at the site of administration or for absorption into the systemic circulation, have been described in the literature. These formulations are designed either for adherence of the dosage form to the skin (for dermal or transdermal delivery of drugs) or mucosal surface (for mucosal or transmucosal delivery of drugs). For skin delivery, formulations generally consist of dermal patches, pastes, band-aids, gels, lotions, sprays, or creams. For mucosal delivery, formulations generally consist of gels, creams, tablets, sprays, or films. In either case, one specific requirement is that the dosage form remains at the administration site for a sufficient amount of time so that the drug may function as needed. A second specific requirement is that the dosage form must consist of pharmaceutically acceptable materials. Many of the reported and commercially available delivery systems intended for topical and mucosal delivery are aqueous-based formulations comprising water-soluble excipients. However, these systems tend to be easily and quickly washed away from the application site within minutes after application. This is very undesirable if the drug must remain at the application site for a prolonged period in order to be efficacious. In an attempt to prolong the residence time at the application site, researchers have described the use of water-insoluble excipients in the formulations. However, most often the use of water-insoluble excipients necessitates the use of non-aqueous solvents to dissolve the excipients. Excessive and repeated administration of non-aqueous solvents is not desirable.
Different types of formulations to deliver drugs topically are known in the art. Specific examples are illustrated below.
U.S. Pat. No. 4,715,369 by Suzuki et al. relates to methods to treat the injured oral mucosa with a thin two-layer tablet comprised of both an adhesive layer and a nonadhesive layer. The adhesive layer is comprised of water-soluble cellulose-based polymers and polyacrylic acid while the nonadhesive layer is comprised mostly of materials with no adhesive properties. The Suzuki patent does not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the Suzuki patent does not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. No. 5,800,832 by Tapolsky et al. relates to a water-soluble, bioerodable device for the delivery of drugs, and specifically dyclonine, to mucosal surfaces. The device comprises an adhesive layer as well as a non-adhesive layer. Both the adhesive layer and the nonadhesive layer consist of water-soluble polymers such as cellulose-based polymers. The Tapolsky patent does not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the Tapolsky patent does not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. No. 5,955,097 by Tapolsky et al. relates to a non water-soluble gel, which adheres to mucosal surfaces and body tissues upon application and forms a film. The gel comprises at least one water-insoluble cellulose-based polymer, a non-aqueous solvent, and at least one active pharmaceutical. The patent teaches that upon application to the mucosal surface or skin, the non-aqueous solvent, primarily ethanol, evaporates, diffuses, or penetrates the surrounding tissue, resulting in precipitation of the non water-soluble polymers into films. The Tapolsky patent further teaches the use of 50 to 80% ethanol by weight in the pharmaceutical gel. The Tapolsky patent does not teach the use of film-forming gels containing at least 25% water by weight and comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the Tapolsky patent does not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. No. 5,780,045 by McQuinn et al. relates to a transmucosal drug delivery device in the form of a sheet comprising an acid-containing particulate polymer dispersed in a polytetrafluoroethylene support matrix. The McQuinn patent does not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the McQuinn patent does not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. No. 4,552,751 by Inaba et al. relates to the preparation of multi-layered films of three, five, or seven layers for the administration of specific prostaglandins to mucosal sites. The Inaba patent does not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the Inaba patent does not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. No. 4,517,173 by Kizawa et al. relates to a film preparation consisting of at least three layers, including a pharmaceutical layer, a poorly water-soluble layer, and an intermediate layer. The pharmaceutical layer consists of predonisolone and allantoin together with a water-soluble cellulose-based polymer. The poorly water-soluble layer consists of shellack or fatty acids. The Kizawa patent does not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the Kizawa patent does not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. No. 5,192,802 by Rencher describes the use of a bioadhesive teething gel comprising benzocaine, sodium carboxy methyl cellulose; an agent selected from the group consisting of xanthan gum and sodium alginate and a diluent selected from the group consisting of polyethylene glycol and polyethylene glycol with glycerine. U.S. Pat. No. 5,314,915 by Rencher and U.S. Pat. No. 5,298,258 by Akemi et al. also describe the use of aqueous or oil-based bioadhesive gelling agents. These patents do not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, these patents do not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. Nos. 5,081,157 and 5,081,158 by Pomerantz relate to a film-forming composition for topical application of medicaments to body tissues. The film-forming composition includes hydroxypropyl cellulose, a volatile solvent, and an esterification agent which reacts with the hydroxypropyl cellulose to form a reaction product which is soluble in the solvent. These patents do not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, these patents do not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
U.S. Pat. No. 4,900,554 by Yanagibashi et al. relate to the use of a device for the delivery of drugs in the oral cavity. The device comprises an adhesive layer consisting of at least one acrylic acid polymer, a water-insoluble cellulose derivative, and a pharmaceutical preparation, and a water-insoluble or sparingly soluble backing layer. Yanagibashi et al. state that “it is impossible to achieve an adhesive device for application to body tissue without all three components, that is, acrylic acid polymer, water insoluble cellulose derivative and water insoluble or sparingly soluble backing layer”. The Yanagibashi patent does not teach the use of film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the Yanagibashi patent does not teach the use of pH-sensitive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.
As illustrated, the references described above appear to lack preferred compositions and properties for an efficacious and pharmaceutically acceptable bioadhesive delivery system. Namely, the references do not describe primarily aqueous-based film-forming gels comprised of pH-sensitive polymers and water-insoluble mucoadhesive polymers that form films due to changes in pH and/or desolvation of the polymers. Further, the references do not describe pH-sensitive mucoadhesive wax-film composites intended to remain adhered to the skin or mucosal surface for a prolonged period of time.